Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/9581
Title: Antiplasmodial activity of chloroquine analogs against chloroquine-resistant parasites, docking studies and mechanisms of drug action
Authors: Souza, Nicolli Bellotti de
Carmo, Arturene Maria Lino
Silva, Adilson David de
França, Tanos Celmar Costa
Krettli, Antoniana Ursine
Affilliation: Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Malária. Belo Horizonte, MG, Brazil
Universidade Federal de Juiz de Fora. Instituto de Ciências Exatas. Departamento de Química. Juiz de Fora, MG, Brazil
Universidade Federal de Juiz de Fora. Instituto de Ciências Exatas. Departamento de Química. Juiz de Fora, MG, Brazil
Instituto Militar de Engenharia. Laboratório de Modelagem Molecular Aplicada à Defesa Química e Biológica. Rio de Janeiro, RJ, Brazil
Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Malária. Belo Horizonte, MG, Brazil
Abstract: Background: Given the threat of resistance of human malaria parasites, including to artemisinin derivatives, new agents are needed. Chloroquine (CQ) has been the most widely used anti-malarial, and new analogs (CQAns) presenting alkynes and side chain variations with high antiplasmodial activity were evaluated. Methods: Six diaminealkyne and diaminedialkyne CQAns were evaluated against CQ-resistant (CQ-R) (W2) and CQ-sensitive (CQ-S) (3D7) Plasmodium falciparum parasites in culture. Drug cytotoxicity to a human hepatoma cell line (HepG2) evaluated, allowed to calculate the drug selectivity index (SI), a ratio of drug toxicity to activity in vitro. The CQAns were re-evaluated against CQ-resistant and -sensitive P. berghei parasites in mice using the suppressive test. Docking studies with the CQAns and the human (HssLDH) or plasmodial lactate dehydrogenase (PfLDH) enzymes, and, a β-haematin formation assay were performed using a lipid as a catalyst to promote crystallization in vitro. Results: All tested CQAns were highly active against CQ-R P. falciparum parasites, exhibiting half-maximal inhibitory concentration (IC50) values below 1 μΜ. CQAn33 and CQAn37 had the highest SIs. Docking studies revealed the best conformation of CQAn33 inside the binding pocket of PfLDH; specificity between the residues involved in H-bonds of the PfLDH with CQAn37. CQAn33 and CQAn37 were also shown to be weak inhibitors of PfLDH. CQAn33 and CQAn37 inhibited β-haematin formation with either a similar or a 2-fold higher IC50 value, respectively, compared with CQ. CQAn37 was active in mice with P. berghei, reducing parasitaemia by 100%. CQAn33, -39 and -45 also inhibited CQ-resistant P. berghei parasites in mice, whereas high doses of CQ were inactive. Conclusions: The presence of an alkyne group and the size of the side chain affected anti-P. falciparum activityin vitro. Docking studies suggested a mechanism of action other than PfLDH inhibition. The β-haematin assay suggested the presence of an additional mechanism of action of CQAn33 and CQAn37. Tests with CQAn34, CQAn37, CQAn39 and CQAn45 confirmed previous results against P. berghei malaria in mice, and CQAn33, 39 and 45 were active against CQ-resistant parasites, but CQAn28 and CQAn34 were not. The result likely reflects structure-activity relationships related to the resistant phenotype.
Keywords: Malaria
Chloroquine analogs
Diaminealkyne
P. falciparum
Lactate-dehydrogenase enzyme
Docking
Issue Date: 2014
Publisher: Biomed Central Ltda
Citation: SOUZA, Nicolli Bellotti de et al. Antiplasmodial activity of chloroquine analogs against chloroquine-resistant parasites, docking studies and mechanisms of drug action. Malaria Journal, v. 13, p. 469, 2014
DOI: 10.1186/1475-2875-13-469
ISSN: 1475-2875
Copyright: open access
Appears in Collections:MG - IRR - Artigos de Periódicos

Files in This Item:
File Description SizeFormat 
2014_121.pdf1.24 MBAdobe PDFView/Open



FacebookTwitterDeliciousLinkedInGoogle BookmarksBibTex Format mendeley Endnote DiggMySpace

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.